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PreprintCited by 360Genetic Associations and EpidemiologyForensic and Genetic ResearchGenetic and phenotypic traits in livestock

Signals of polygenic adaptation on height have been overestimated due to uncorrected population structure in genome-wide association studies

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Sohail, Mashaal, Maier, Robert M., Ganna, Andrea, Bloemendal, Alex, Martin, Alicia R., Turchin, Michael C., Chiang, Charleston W. K., Hirschhorn, Joel N. +6 more·2018·eLife
DOI 10.1101/355057PMC PMC6428571

Preprint — published as 10.7554/elife.39702 · Paper page

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Abstract

Genetic predictions of height differ among human populations and these differences are too large to be explained by genetic drift. This observation has been interpreted as evidence of polygenic adaptation. Differences across populations were detected using SNPs genome-wide significantly associated with height, and many studies also found that the signals grew stronger when large numbers of subsignificant SNPs were analyzed. This has led to excitement about the prospect of analyzing large fractions of the genome to detect subtle signals of selection and claims of polygenic adaptation for multiple traits. Polygenic adaptation studies of height have been based on SNP effect size measurements in the GIANT Consortium meta-analysis. Here we repeat the height analyses in the UK Biobank, a much more homogeneously designed study. Our results show that polygenic adaptation signals based on large numbers of SNPs below genome-wide significance are extremely sensitive to biases due to uncorrected population structure.

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  • Comparisons of geographically stratified phenotypes like height across populations with highly divergent genetic backgrounds and mean environmental differences are especially prone to confounding from correlated environmental and genetic divergence.

    “Comparisons of geographically stratified phenotypes like height across populations with highly divergent genetic backgrounds and mean environmental differences, such as differences in resource abundance during development across continents, are especially prone to confounding from correlated environmental and genetic divergence43,44.”

    From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [43]

    The Results (lines 101–111) and Discussion (lines 365–386; page unavailable) show that population structure can distort comparisons of genetic height scores and create misleading signals across populations. The paper examines predominantly European genetic comparisons; it does not establish the claim’s more specific account of correlated environmental and genetic divergence across continents, including differences in developmental resources. (LLM, conf=0.84)

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  • Evidence of polygenic adaptation and/or its relative magnitude for height is under question.

    “These effects are particularly challenging to disentangle, as has clearly been demonstrated for height, where evidence of polygenic adaptation and/or its relative magnitude is under question43,44.”

    From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [43]

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Research works printed but not linked: 30

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Authors
Sohail, M., Maier, R. M., Ganna, A., Bloemendal, A., Martin, A. R., Turchin, M. C., Chiang, C. W. K., Hirschhorn, J. N., Daly, M. J., Patterson, N., Neale, B. M., Mathieson, I., Reich, D., & Sunyaev, S. R.
Affiliations
  • Broad Institute (US)
  • Brown University (US)
  • University of Southern California (US)
  • University of Pennsylvania (US)
ORCID
Venue
eLife
Publisher
openRxiv
Published
2018-06-25
Volume
8
ISSN
2050-084X (ISSN-L)
DOI
10.1101/355057
PMC
PMC6428571
OpenAlex
W2924359406
Cited by
360
References
0
Citations by year
2026: 28 · 2025: 30 · 2024: 35 · 2023: 36 · 2022: 61 · 2021: 63 · 2020: 58 · 2019: 41 · 2018: 7
FWCI
33.45
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Työväentutkimus Vuosikirja (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Alfred P. Sloan Foundation
  • Allen Foundation
  • Charles E. Kaufman Foundation
  • National Institutes of Health
  • Allen Discovery Center
  • National Institute of Mental Health (R01MH101244)
  • National Human Genome Research Institute (R01HG006399, U01HG009088)
  • National Institute of General Medical Sciences (R01GM100233, R35GM127131)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075787)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
Keywords
polygenic adaptation, height, population stratification, polygenic risk score, UK Biobank, genetic effect size
MeSH terms
Adaptation, Biological, Body Height, United Kingdom, Humans, Phylogeny, Databases, Factual, Computational Biology, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Biostatistics

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